Udo Schnupf

DFTMD studies of glucose and epimers: anomeric ratios, rotamer populations, and hydration energies

Results are presented from density functional molecular dynamics (DFTMD) simulations, based on constant energy dynamics, of glucose and its cyclic form of 6-carbon epimers. Both in vacuo and an implicit solvent method (COSMO) were examined, including simulations of low-energy conformations of each molecule. Analysis of the DFTMD results includes the following: energies averaged over the simulation time, calculated anomeric ratios, hydroxyl and hydroxymethyl rotamer populations, and hydration energies. Hydrogen-bonding networks persistence times were examined, and the effects of solvation on rotamer populations were described. Anomeric ratios calculated from energy optimization of an ensemble of low-energy conformers are compared to those obtained from ensemble averages from molecular dynamics, with dynamics simulations giving populations in best agreement with experimental anomeric ratios. Ensemble results in vacuo were not in agreement with experimental anomeric ratios or hydroxymethyl populations, producing in some cases reversal of the alpha:beta ratios. The difficulty in obtaining correct alpha:beta ratios increases with the number of axial groups; the mono-axial epimers being best represented, epimers with two axial groups being more difficult, and the epimers with three axial hydroxyl groups being most difficult to analyze, the result of a large number of very strong hydrogen-bonding networks that form the ensemble of low-energy conformations in the multi-axial structures.

DFT conformational studies of α‐maltotriose

Recent DFT optimization studies on α‐maltose improved our understanding of the preferred conformations of α‐maltose. The present study extends these studies to α‐maltotriose with three α‐D‐glucopyranose residues linked by two α‐[1→4] bridges, denoted herein as DP‐3s. Combinations of gg, gt, and tg hydroxymethyl groups are included for both “c” and “r” hydroxyl rotamers. When the hydroxymethyl groups are for example, gg‐gg‐gg, and the hydroxyl groups are rotated from all clockwise, “c”, to all counterclockwise, “r”, the minimum energy positions of the bridging dihedral angles (ϕH and ψH) move from the region of conformational space of (−, −), relative to (0°, 0°), to a new position defined by (+, +). Further, it was found previously that the relative energies of α‐maltose gg‐gg‐c and “r” conformations were very close to one another; however, the DP‐3s relative energies between hydroxyl “c” or “r” rotamers differ by more than one kcal/mol, in favor of the “c” form, even though the lowest energy DP‐3 conformations have glycosidic dihedral angles similar to those found in the α‐maltose study. Preliminary solvation studies using COSMO, a dielectric solvation method, point to important solvent contributions that reverse the energy profiles, showing an energy preference for the “r” forms. Only structures in which the rings are in the chair conformation are presented here.

27 ps DFT molecular dynamics simulation of α‐maltose: A reduced basis set study

DFT molecular dynamics simulations are time intensive when carried out on carbohydrates such as α‐maltose. In a recent publication (Momany et al., J. Mol. Struct. THEOCHEM, submitted) forces for dynamics were generated from B3LYP/6‐31+G* electronic structure calculations. The implicit solvent method COSMO was applied to simulate the solution environment. Here we present a modification of the DFT method that keeps the critical aspects of the larger basis set (B3LYP/6‐31+G*) while allowing the less‐essential atom interactions to be calculated using a smaller basis set, thus allowing for faster completion without sacrificing the interactions dictating the hydrogen bonding networks in α‐maltose. In previous studies, the gg′‐gg‐c solvated form quickly converged to the “r” form during a 5 ps dynamics run. This important conformational transition is tested by carrying out a long 27 ps simulation. The trend for the “r” conformer to be most stable during dynamics when fully solvated, is confirmed, resulting in ∼20/80% c/r population. Further, the study shows that considerable molecular end effects are important, the reducing end being fairly stable, the O6H pointing at the O5, while the nonreducing end moves freely to take on different conformations. Some “kink” and transition state forms are populated during the simulation. The average H1′···H4 distance of 2.28 Å confirms that the syn form is the primary glycosidic conformation, while the average C1′O1′C4 bond angle was 118.8°, in excellent agreement with experimental values. The length of this simulation allowed the evaluation of vibrational frequencies by Fourier transform of the velocity correlation function, taken from different time segments along the simulation path.